D-3-phosphoglycerate dehydrogenase (PHGDH) (PHGDH)

D-3-phosphoglycerate dehydrogenase (PHGDH) is the primary enzyme responsible for initiating the de novo serine biosynthesis pathway by converting the glycolytic intermediate 3-phosphoglycerate into 3-phosphohydroxypyruvate (UniProt O43175). This metabolic step is vital for generating serine, which serves as a precursor for glycine, cysteine, and various phospholipids, and is a key contributor to the one-carbon metabolism required for nucleotide synthesis (PubMed: 26878235). PHGDH is frequently upregulated in several cancers, most notably triple-negative breast cancer and melanoma, where its activity supports the high biosynthetic demands and antioxidant requirements of proliferating cells (PubMed: 21666678). In contrast, genetic deficiency of PHGDH leads to severe congenital neurological disorders, such as Neu-Laxova syndrome, characterized by microcephaly and skin abnormalities, underscoring its importance in brain development (PubMed: 25085400). Pharmacological inhibition of PHGDH using small molecules like NCT-503 or CBR-5884 has shown promise in preclinical models by reducing tumor growth through the depletion of intracellular serine and glycine (PubMed: 26878234). However, the potential for systemic toxicity, particularly regarding neurological function and the maintenance of D-serine levels in the brain, remains a significant consideration in the development of PHGDH-targeted therapies.

Other names

3-phosphoglycerate dehydrogenase3-PGDHPhosphoglycerate dehydrogenasePHGDH

Inhibition of the catalytic activity of PHGDH to deplete intracellular serine and glycine levels, thereby impairing nucleotide synthesis and antioxidant capacity in cancer cells.